Pharmacological Research 130 (2018) 259–272

Contents lists available at ScienceDirect

Pharmacological Research
journal homepage: www.elsevier.com/locate/yphrs

Review

Tocotrienols: The promising analogues of vitamin E for cancer

therapeutics
Bethsebie Lalduhsaki Sailo, Kishore Banik, Ganesan Padmavathi, Monisha Javadi,
Devivasha Bordoloi, Ajaikumar B. Kunnumakkara ∗,1,2
Cancer Biology Laboratory and DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering,
Indian Institute of Technology Guwahati, Guwahati, Assam, 781039, India

a r t i c l e i n f o a b s t r a c t

Article history: Despite the significant advancements in the diagnosis and treatment of cancer, it still remains one of
Received 14 November 2017 the most fatal diseases in the world due to the lack of sensitive diagnosis methods and effective drugs.
Received in revised form 6 February 2018 Therefore, discovering novel therapies that are safe, efficacious and affordable are required for the bet-
Accepted 12 February 2018
ter management of this disease. Tocotrienols, analogues of vitamin E have gained increased attention
Available online 27 February 2018
due to their safety and efficacy. Extensive research over the past several years has strongly indicated
that tocotrienols can efficiently prevent/inhibit the growth of different cancers such as cancers of blood,
Keywords:
brain, breast, cervical, colon, liver, lung, pancreas, prostate, skin, stomach etc. This is mainly accredited
Tocotrienols
Cancer
to their ability to modulate various molecular targets involved in cancer cell proliferation, survival, inva-
Chemoprevention sion, angiogenesis, and metastasis such as NF-␬B, STAT3, Akt/mTOR, etc. In addition, increasing lines
Chemosensitization of evidence has shown that tocotrienols can sensitize cancer cells to chemotherapeutic agents such as
Molecular targets celecoxib, doxorubicin, erlotinib, gefitinib, gemcitabine, paclitaxel, statin etc. Moreover, several clinical
trials have confirmed the safety and tolerability of tocotrienols in humans. This review summarizes the
potential of tocotrienols for the prevention and treatment of different cancers based on the available
in vitro, in vivo and clinical studies.
© 2018 Published by Elsevier Ltd.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
2. Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
3. Tocotrienols are superior to tocopherols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
4. Tocotrienols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
5. Molecular targets of tocotrienols in cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
6. Tocotrienols as chemopreventive and chemotherapeutic agents for various cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
6.1. Breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
6.2. Colorectal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
6.3. Gastric cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
6.4. Glioblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
6.5. Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
6.6. Liver cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
6.7. Lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
6.8. Mesothelioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265

∗ Corresponding author at: Cancer Biology Laboratory and DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengi-
neering, Indian Institute of Technology Guwahati, Room # 005, O-Block, Guwahati, Assam, 781039, India.
E-mail address: kunnumakkara@iitg.ernet.in (A.B. Kunnumakkara).
1
Websites: www.iitg.ernet.in/kunnumakkara.
2
www.iitg.ac.in/kunnumakkara.

https://doi.org/10.1016/j.phrs.2018.02.017
1043-6618/© 2018 Published by Elsevier Ltd.
260 B.L. Sailo et al. / Pharmacological Research 130 (2018) 259–272

6.9. Pancreatic cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266

6.10. Prostate cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
6.11. Skin cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
6.12. Other cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
7. Chemosensitizing effect of tocotrienols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
8. Clinical studies on tocotrienols- completed and ongoing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
9. Conclusions and future prospect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269

1. Introduction higher anti-oxidant activity of T3 is attributed to their structures

that assist in their integration into the cell i.e. short tail, unsatu-
Despite extensive research over the last several decades for find- rated, with three double bonds, whereas T isoforms have saturated
ing a cure for cancer, it continues to remain one of the most fatal side-chain without double bonds (Fig. 1) [4,9]. Moreover, unlike
chronic diseases today. The incidence and mortality rates of can- T isoforms, T3 isoforms are predominant for their innate anti-
cer continue to rise, accounting for approximately 14.1 million cancer and chemosensitizing activities and confer their anti-cancer
new cases and 8.2 million deaths worldwide in 2012 alone [1]. activities independently from its antioxidant function [4,14]. In
Conventional treatment modalities for cancer including surgery, agreement with this, studies have delineated that T3 are more
radiation, and chemotherapy have failed to completely eradicate efficient than T in abrogating various cancer-promoting pathways
cancer. Hence, finding a cure for cancer is the holy grail of medical including 5-lipoxygenase (5-LOX)-catalyzed eicosanoids, cyclooxy-
research. In addition, most of the recently developed therapies are genase (COX), nuclear transcription factor-kappaB (NF-␬B) and
extremely expensive and not affordable to majority of the popula- signal transducer and activator of transcription factor 3 (STAT3),
tion. On account of the alarming increase in cancer incidence and which may be due to the higher absorption of T3 by cancer cells,
the spiraling cost of unsuccessful treatments, cancer prevention attributed to their unsaturated isoprenoid side chain that enhances
and treatment using nutraceuticals has recently become a subject their lipophilic property [15]. Moreover, it has been exhibited that
of immense interest amongst researchers [2]. Further, numerous T3 have greater potency than T in instigating apoptosis and are
studies have evinced that phytochemicals found in fruits, vegeta- found to preferentially accumulate in breast cancer cells as com-
bles, and spices evidently exhibit chemopreventive and therapeutic pared to T [16]. More importantly, it has been demonstrated that
properties against various tumors by modulating different types ␥- and ␦-T3 induced apoptosis in various tumors via distinct mech-
of oncogenic targets such as cytokines, chemokines, growth fac- anisms that are not shared by the T isoforms, such as induction of
tors, inflammatory enzymes, transcription factors etc. [3,4]. Thus, endoplasmic reticulum (ER) stress and increased translocation of
these compounds serve as profound sources of leads for cancer estrogen receptor beta (ER␤) into the nucleus by serving as a lig-
drug development. In line with this, a group of dietary compo- and for ER␤ [17]. Notably, growing body evidence has revealed T3
nents, known as tocotrienols (T3)-analogues of vitamin E have isoforms as potent chemosensitizers, but not T isoforms, thus fur-
entered the limelight in the field of cancer drug development [5–7]. ther validating its higher potency than T. Considering these aspects,
Tocotrienols (T3) are natural anti-oxidants that exhibit stronger T3 are found to be more promising than T for treatment of various
anti-cancer activity than tocopherol (T), the other analogues of cancers.
vitamin E [4].
4. Tocotrienols
2. Vitamin E
The natural vitamin E derivative, T3 was discovered in 1956. The
Vitamin E is a group of hydrophobic lipid-soluble compounds name “tocotrienol” was first proposed by Bunyan et al. to signify the
consisting of eight isoforms [8]. It was first discovered in 1922 as an isoprenoid side chain detected when it was isolated from the latex
essential fertility factor. Since its discovery, it has been considered of the rubber plant, Hevea brasiliensis. The anti-cancer property of
as one of the most potent anti-oxidants, neutralizing free radicals by T3 was identified and studied since 1985 [13,18]. The four isomers
donating hydrogen from its chromanol ring [9]. Vitamin E is abun- of T3 are distinguished based on the number and position of methyl
dantly found in edible oils including oils of barley, coconut, rice groups on the chromanol rings i.e. ␣-T3 is 5, 7, 8, trimethyl; ␤-T3
bran, palm, wheat etc. [10]. Vitamin E is primarily grouped into two is 5, 8, dimethyl; ␥-T3 is 7, 8, dimethyl and ␦-T3 is 8, monomethyl
categories namely, tocopherols (T) and tocotrienols (T3), each con- (Fig. 1) [10]. The T3 isoforms are mostly found at high concentra-
sisting of four isoforms namely: ␣-, ␤-, ␥- and ␦- (Fig. 1) [8,10,11]. tion in palm oil, rice bran oil and cereal grains including barley,
Tocopherols (T) are the saturated isoforms of vitamin E whereas oats, wheat, etc. [4]. Pharmacokinetics studies of T3 in rats sug-
tocotrienols (T3) are the unsaturated isoforms with isoprenoid side gested that oral administration provide the highest bioavailability
chain [10]. rate although the absorption was incomplete, whereas intramus-
cular and intraperitoneal routes of administration have negligible
3. Tocotrienols are superior to tocopherols absorption. However, among the isoforms, ␣-T3 has the highest
bioavailability, showing absolute bioavailability 28% while ␥-T3
Over past several decades, majority of vitamin E research was and ␦-T3 has 9%. A phase I enzyme cytochrome p450 3A4 (CYP3A4)
focused on ␣-tocopherol (␣T) isoform, as it was considered as the and P-glycoprotein of the gastrointestinal epithelium are associ-
most potent anti-oxidant isoform whereas only about 3% of the ated with oral absorption of T3 [10,19]. In addition, the unsaturated
study has been carried out for the T3 isoforms [9,12]. However, isoprenoid side chain of T3 contributes to their enhanced absorp-
accumulating preclinical and clinical studies have significantly tion into fatty tissues of the brain and liver and their distribution
proven that T3 display stronger anti-oxidant, anti-inflammatory, on the plasma membranes [9]. Further, the biological half-life (t1/2 )
and chemopreventive activities when compared with T [9,13]. The of ␣-T3, ␥-T3, and ␦-T3 in humans was determined as 4.4, 4.3,
 B.L. Sailo et al. / Pharmacological Research 130 (2018) 259–272
Fig. 1. Structures of different analogues of Vitamin E. The figure has been made according to Roskoski et al. [188].
and 2.3 h, respectively [19]. Accumulated findings have strongly
established T3 as analgesic, anti-ageing, anti-bacterial, anti-
cancer, anti-cholesterolemic, anti-diabetic, anti-hyperlipidemic,
anti-inflammatory, anti-oxidant, anti-pyretic, anti-thrombotic,
cardioprotective, chemopreventive, gastroprotective, hepatopro-
tective, and neuroprotective agents and are found to improve
cognition, bone density etc. [4,10,13,20,21]. The anti-oxidant activ-
ity of T3 is facilitated by activation of anti-oxidant enzymes such
as superoxide dismutase (SOD), NADPH: quinone oxidoreductase
(NQO) and glutathione peroxidase (GPX) that scavenge free radi-
cals. In addition, studies have shown that T3 isoforms exert their
anti-cancer effect in cancer cells of the breast, colon, liver, lung, skin,
stomach, pancreas, prostate etc. [10]. Among the four T3 isoforms,
␥- and ␦-T3 were found to exhibit stronger anti-cancer activity [13].
The anti-cancer activity of T3 is mediated via induction of apopto-
sis, modulation of cell cycle progression, inhibition of angiogenesis,
metastasis etc. [22–24]. Moreover, combination of T3 with several
chemotherapeutic drugs such as celecoxib, gefitinib, gemcitabine,
statins, or dietary components such as curcumin, polyphenols,
sesamin, etc. effectively sensitized the cancer cells to these agents
[25]. Above all, several clinical trials have proven the efficacy, safety
and tolerability of T3 [26–28].
5. Molecular targets of tocotrienols in cancer
Aforementioned, T3 exert several inherent anti-cancer activi-
ties including anti-inflammatory, anti-proliferative, anti-survival,
anti-angiogenic properties etc., which are mediated via the reg-
ulation of multiple signaling pathways associated with cancer
[29–32]. For instance, T3 were found to exert anti-inflammatory
activity by suppressing COX-2, hypoxia-inducible factor-1 (HIF-1),
inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2),
and interleukin (IL)-1,-6 and -8 [10,33]. Increasing lines of evidence
has ascertained that the anti-cancer activity of T3 was primarily
mediated by the inhibition of two important transcription fac-
tors, NF-␬B and STAT3 and their regulated gene products [3]. For
example, T3 was shown to inhibit the tumor necrosis factor-alpha
(TNF-␣)-induced NF-␬B activation, which resulted in the downreg-
ulation of its related gene products that are involved in cell survival
including inhibitors of apoptosis proteins (IAP)-1, −2, B-cell lym-
261
phoma 2 (Bcl-2), B-cell lymphoma-extra large (Bcl-xL), cellular
FLICE-like inhibitory protein (cFLIP), X-linked inhibitor of apopto-
sis (XIAP), survivin etc. [3,34]. Moreover, T3 inhibited Src kinase,
Janus kinase (JAK) 1, and JAK2, which are the regulators of STAT3,
thus eventually downregulating STAT3 (Fig. 2) [3,35]. Notably, T3
inhibited cancer cell proliferation by downregulating 3-hydroxy-3-
methylglutaryl coenzyme A reductase (HMGCR), cyclin-dependent
kinases (CDK)-2, −4, −6, c-Jun, c-Myc, mitogen-activated protein
kinases (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, Wnt/␤-
catenin etc. [10,33,36–41]. Alternatively, T3 were also reported to
induce growth arrest and apoptosis by activating CDK inhibitors
(p21, p27, p53), caspase-3, -8, -9, Bcl-2-associated X (Bax) and
enhancing cleavage of Bid, Apaf-1, Fas, etc. [10,33]. Additionally,
T3 were found to downregulate angiopoietin-1, fibroblast growth
factor (FGF), metalloproteinase-9 (MMP-9), TNF-␣, and vascular
endothelial growth factor (VEGF), thereby inhibiting angiogenesis
in cancer [10,33,42].
6. Tocotrienols as chemopreventive and chemotherapeutic
agents for various cancers
Kato et al. first reported the anti-cancer potential of T3 in 1985,
where ␣-T3 was shown to increase the life span of tumor-bearing
rats [18]. Subsequently, numerous investigations have evinced the
anti-cancer potential of T3 in cancers of the breast, colorectal,
liver, lung, pancreas, prostate, stomach etc. The next section of this
review will focus on the various preclinical and clinical findings of
T3 against different cancers (Tables 1–3).
6.1. Breast cancer
Observational studies have suggested that vitamin E from
dietary sources may prevent breast cancer in women [178]. Sup-
porting this fact, accumulating evidence has substantiated that T3
exhibited chemopreventive and anti-cancer activity against breast
cancer both in vitro and in vivo (Fig. 2). For instance, T3 has been
shown to reduce the growth of both estrogen-receptor-positive
(ER+) and estrogen-receptor-negative (ER-) phenotypes of breast
cancer cells by inhibiting HMGCR activity [48,179–181]. In addi-
tion, it has also been proven that ␣-, ␥- and ␦-T3 suppressed the
262 B.L. Sailo et al. / Pharmacological Research 130 (2018) 259–272

Table 1
Tocotrienols Against Different Cancers.

Cancer In vitro/ in vivo Cell line/ Model Mechanism of action Reference

Bladder Cancer In vitro T24, 5637; J82; UMUC-3 ↓STAT3 [43]

Breast Cancer In vitroc T47D ↓Exosome heregulin [44]
Breast Cancer In vitroc MCF-7/Adr ↓P-gp [45]
Breast Cancer In vitroc MDA-MB-231; T-47D; MCF-10A ↓Wnt/␤-catenin [41]
Breast Cancer In vitroc SKBR3; BT474 ↓HER2 [46]
Breast Cancer In vitroc +SA ↓Rac1/WAVE2 [47]
Breast Cancer In vitro MCF-7; T47D; MDA-MB-23 ↓HMGR [48]
Breast Cancer In vitroc MCF-7; MDA-MB-231 ↑ER stress [6]
Breast Cancer In vitro MDA-MB-231; MDA-MB-468 ↑miRNA-429 [49]
Breast Cancer In vitro MCF-7 ↓RAS/ERK [50]
Breast Cancer In vitro +SA; MCF-7 ↓c-Myc [51]
Breast Cancer In vitroc +SA; MCF-7 ↓Akt/mTOR; ↓c-Myc [52]
Breast Cancer In vitroc +SA; MCF-7; MDAMB-231 ↓Akt/mTOR [53]
Breast Cancer In vivoi +SAj ↓Akt/mTOR [54]
Breast Cancer In vitro MDA-MB-231; MCF-7 ↓NF-␬B [55]
Breast Cancer In vitro SKBR3 ↑ROS [56]
Breast Cancer In vivo HER-2/neuk ↑HER-2/neu [56]
Breast Cancer In vitro – ↓PI3K/Akt [57]
Breast Cancer In vitrod SKBR3 ↓p38; ↓ERK1/2 [58]
Breast Cancer In vitrod,e 4T1 ↓IL-8; ↓VEGF [42]
Breast Cancer In vitroc MCF-7; MDA-MB 231 ↑ER stress [59]
Breast Cancer In vitroc – ↑JNK/CHOP/DR5 [60]
Breast Cancer In vitroc +SA ↓HGF; ↑Met [61]
Breast Cancer In vitro MCF-7 ↓AP15; ↑MIG6 [62]
Breast Cancer In vitroc,d SKBR3; MCF-7 ↑p53; ↑p21; ↑p16 [63]
Breast Cancer In vitroc MCF-7 ↑NQO2 [64]
Breast Cancer In vitroe MCF-7 ↑ER-␤ [65]
Breast Cancer In vitroc MCF-7; MDA-MB-231 ↓Id1 [66]
Breast Cancer In vitroc +SA ↓G1-S progression [30]
Breast Cancer In vitroa,c,d MDA-MB-231; MCF-7 ↑NRF2; ↓KEAP1 [67]
Breast Cancer In vitro MDA-MB-231; MCF-7 ↑JNK; ↑p38 MAPK; ↑DR5 [68]
Breast Cancer In vitrod,e 4T1 ↑IL-24; ↓VEGF; ↓IL-8 [69]
Breast Cancer In vivo 4T1j ↑IL-24 [69]
Breast Cancer In vitro MDA-MB-231 ↑ER-␤ [70]
Breast Cancer In vitro +SA ↑ER stress [71]
Breast Cancer In vivoe 4T1j ↓VEGF [72]
Breast Cancer In vitrod MDA-MB-231 ↓Cyclin D1; ↓pRb [73]
Breast Cancer In vitroc MCF-7 ↓NF-␬B [34]
Breast Cancer In vitroc +SA ↓PI3K/Akt [74]
Breast Cancer In vitroc – ↓Pl3K/PDK-1/ Akt [75]
Breast Cancer In vitro +SA ↓PI3K/PDK/Akt [76]
Breast Cancer In vitroc +SA ↑Bcl-2; ↑Bcl-xL [77]
Breast Cancer In vitroc +SA ↓Akt; ↓NF-␬B [78]
Breast Cancer In vitro MCF-7; MDA-MB 231 ↑MM1; ↑IFITM-1 [79]
Breast Cancer In vivo MCF-7l ↓c-Myc [80]
Breast Cancer In vitroc MDA-MB-231 ↑Mitochondrial disruption [81]
Breast Cancer In vitro +SA ↑Caspase-8 [82]
Breast Cancer In vitrod MDA-MB-435 ↑TGF- ␤ receptor II; ↑TGF-b, Fas, JNK [83]
Breast Cancer In vivoe DMBAm ↓HMG-CoA [84]
Breast Cancer In vitro CL-S1; -SA; +SA ↑DNA fragmentation [16]
Breast Cancer In vitro MCF-7; MDA-MB 435 ↑DNA fragmentation [85]
Cervical Cancer In vitroc HeLa ↑G0 /G1 cell cycle arrest [86]
Cervical Cancer In vitroc,d HeLa ↑ER stress [87]
Cervical Cancer In vitro HeLa ↑IL-6; ↓Cyclin D3; ↓p16; ↓CDK6 [31]
Colorectal Cancer In vivoc HCT 116n ↓NF-␬B [88]
Colorectal Cancer In vivoe SW620n ↓Wnt [38]
Colorectal Cancer In vitrod DLD-1 ↑Caspases; ↓pAkt [89]
Colorectal Cancer In vivof DLD-1l ↑p21; ↑p27; ↑Caspase-3, -9; ↓pAkt [89]
Colorectal Cancer In vitroc SW620 ↓Wnt [39]
Colorectal Cancer In vitro SW620 ↓Wnt [40]
Colorectal Cancer In vitroc HT-29 ↓␤-catenin/Tcf [90]
Colorectal Cancer In vitroc SW620 ↓Wnt [91]
Colorectal Cancer In vitroc HT-29 ↑Bax/ Bcl-2 ratio [92]
Colorectal Cancer In vitrod DLD-1 ↓HIF-1␣ [93]
Colorectal Cancer In vitrod DLD-1 ↓PI3K/PDK/Akt [94]
Colorectal Cancer In vivod DLD-1l ↓PI3K/PDK/Akt [94]
Colorectal Cancer In vitro DLD-1 ↓Telomerase activity [95]
Colorectal Cancer In vitroe RKO ↑p53 [96]
Gastric Cancer In vitroc SGC-7901 ↓ERK1/2 [97]
Gastric Cancer In vitro SGC-7901 ↓MMP-2, -9 [98]
Gastric Cancer In vitro SGC-7901 ↓␤-catenin [99]
Gastric Cancer In vitroc SGC-7901 ↑Caspase-3, -9 [100]
Gastric Cancer In vitro SGC-7901 ↓MAPK [101]
Glioblastoma In vitrob U87MG ↑Caspase-8 [102]
 B.L. Sailo et al. / Pharmacological Research 130 (2018) 259–272 263

Table 1 (Continued)

Cancer In vitro/ in vivo Cell line/ Model Mechanism of action Reference

Glioblastoma In vitro U87MG ↑Caspase-8 [103]

Leukemia In vitroc,d CEM-SS ↑Nuclear fragmentation [12]
Leukemia In vitroc HL- 60; NB-4; Raji; SY-5Y ↑Caspase; ↑Cyt.c; ↑Bid cleavage [104]
Leukemia In vitroc KBM-5 ↓NF-␬B [34]
Liver Cancer In vitroc HepG2 ↑Peroxiredoxin-4 [105]
Liver Cancer In vivo HCCLM3 Luc2o ↓Akt/ mTOR [106]
Liver Cancer In vitroc HepG2; C3A; SNU-38; PLC/PRF5 ↓STAT3 [107]
Liver Cancer In vitro HepG2 ↓TG; ↓VLDL secretion [108]
Liver Cancer In vitro MH134 ↑ PARP fragmentation [109]
Liver Cancer In vivo MH134p ↑PARP fragmentation [109]
Liver Cancer In vitro Hep3B ↑Caspase-8, -9 [110]
Liver Cancer In vitrod HepG2 ↑S phase arrest [111]
Liver Cancer In vivo 4NQOq ↑S phase arrest [111]
Liver Cancer In vitro BNL 1ME A.7R.1 ↑Caspase 3; ↑DNA fragmentation [112]
Liver Cancer In vitro dRLh-84 ↑Caspase-3 [113]
Liver Cancer In vivo DEN & AAFr ↓GSH-Px; ↓GST; ↓GSSG-Rx [114]
Liver Cancer In vivo AAFr ↓GGT; ↓UDP-GT [115]
Lung Cancer In vitrob A549 ↑Caspase-8 [102]
Lung Cancer In vitro - ↑Caspase-8 [103]
Lung Cancer In vitrod A549; H1650 ↓Notch-1 [116]
Lung Cancer In vitro A549 ↓Akt; ↓HIF-2␣ [117]
Lung Cancer In vitroc H1299 ↓NF-␬B [34]
Lung Cancer In vitrog A549 ↓Ras & RhoA prenylation [118]
Mesothelioma In vitro H2452 ↓Ras [119]
Mesothelioma In vitro H2452 ↓HIF-2␣ [120]
Mesothelioma In vitrog H28 ↓STAT [121]
Multiple myeloma In vitroc U266; MM.1R, MM.1S ↓STAT3 [35]
Multiple myeloma In vitroc U266 ↓NF-␬B [34]
Neuroblastoma In vitroc SH-SY5Y ↑Caspase-9 [122]
Oral Cancer In vitroc SCC-4 ↓NF-␬B [34]
Pancreatic Cancer In vitrod L3.6pl; MIAPaCa-2 ↓VEGF; ↓MMP-9 [123]
Pancreatic Cancer In vivod L3.6plo ↓MMP-9 [123]
Pancreatic Cancer In vitrod MIA PaCa-2 ↑Bax [124]
Pancreatic Cancer In vitrod MIA PaCa-2; SW1990; BxPC-3 ↑p27(Kip1); ↓RAS-MEK-ERK [125]
Pancreatic Cancer In vivod MIA PaCa-2n ↑p27(Kip1); ↓pMAPK [125]
Pancreatic Cancer In vivo LSL-Kras(G12D/+); Pdx-1-Cres ↓MEK/ERK; ↓Akt; ↓NF-kB [126]
Pancreatic Cancer In vitro Panc-1; MIA PaCa-2; BxPC-3 ↓ErbB2 [36]
Pancreatic Cancer In vitroc BxPC-3; MIA PaCa-2; Panc-1 ↓NF-␬B [127]
Pancreatic Cancer In vivo MIA PaCa-2o ↓NF-␬B [127]
Pancreatic Cancer In vitroc MIA PaCa-2; PC3 ↓STAT3 [35]
Pancreatic Cancer In vivoc MIA PaCa-2o ↓STAT3 [35]
Pancreatic Cancer In vitro PANC-1; MIA PaCa-2; BxPC-3 ↓HMGR [128]
Prostate Cancer In vitro PC3 ↓Fyn/HIF-1␣ [129]
Prostate Cancer In vitro VcaP ↑p21; ↑p27 [130]
Prostate Cancer In vivo VCaPn ↑p21; ↑ p27 [130]
Prostate Cancer In vitro PC-3 ↓Src; ↓STAT3 [131]
Prostate Cancer In vitro PC-3; LNCaP ↑DHS; ↑DHC [132]
Prostate Cancer In vivo LNCaPn ↑DHS; ↑DHC [132]
Prostate Cancer In vitro CHO-7; SRD-15 ↓SREBP-2 [133]
Prostate Cancer In vitro PC-3; CRL-1435; LNCaP; CRL-1740 ↓TGF␤2 [134]
Prostate Cancer In vitro PC-3; DU145 ↓CD133/CD44 [135]
Prostate Cancer In vitrod PCa ↓NF-␬B; ↓EGFR [136]
Prostate Cancer In vitroe LNCaP; DU145; PC-3 ↑G0/ G1 cell cycle arrest [137]
Skin Cancer In vitrod BLM; A375 ↑ER-stress [138]
Skin Cancer In vivod A375n ↑ER-stress [138]
Skin Cancer In vitro B16 ↑ERK [139]
Skin Cancer In vitro B16F10 ↑Syntaxin7; ↑Vps16; ↑Vps3; ↑Vps41 [140]
Skin Cancer In vitrod A2058; A375 ↑Caspase-3; ↓CDK-4 [141]
Skin Cancer In vitro C32; G361 ↓NF-␬B; ↑JNK [142]

Note: ↑, Upregulation; ↓- Downregulation; AAF - 2-acetylaminofluorene; AP15- Apoptosis inhibitor 5 protein; Bax- BCL2-Associated X; Bcl-2 - B-cell lymphoma 2; Bcl-xL-
B-cell lymphoma-extra large; cAMP-Cyclic adenosine monophosphate; CDK-cyclin-dependent kinase; CDK6- Cyclin-dependent kinase 6; CHOP-CCAAT-enhancer-binding
protein homologous protein; Cyt.c - Cytochrome c; DEN -Diethylnitrosamine; DHC- Dihydroceramide; DHS- Dihydrosphingosine; DMBA- 7,12 Dimethylbenz(a)anthracene;
DR- death-receptor; EGFR-epidermal growth factor receptor; EGR-1-Early growth response protein 1; ER- Endoplasmic reticulum; ER-␤ -Estrogen receptor beta; ErbB-
erb-b2 receptor tyrosine kinase; ERK- extracellular signal–regulated kinase; GGT-gamma-glutamyltranspeptidase; GSSG-Rx-glutathione reductase; GSH-Px-glutathione per-
oxidase; GST- glutathione S-transferase; HER2-Human epidermal growth factor receptor 2; HGF- Hepatocyte growth factor; HIF-Hypoxia-inducible factor; HMGR- HMG-CoA
reductase; ID- inhibitor of DNA binding; ID1, Inhibitor of DNA binding 1; IFITM-1- interferon-inducible protein 9–27; IL-Interleukin; JNK - Jun amino-terminal kinases;
KEAP- Kelch Like ECH Associated Protein; MAPK-Mitogen-activated protein kinases; MIG6-Mitogen-inducible gene-6; MM1- c-Myc binding protein; MMP- Matrix metal-
loproteinases; mTOR- mechanistic target of rapamycin; NF-␬B- nuclear factor kappa-light-chain-enhancer of activated B cells; NQO2-NAD(P)H dehydrogenase quinone 2;
pAkt- phosphorylated Akt; PARP- Poly (ADP-ribose) polymerase; PDK- 3-phosphoinositide dependent protein kinase; PI3K, Phosphatidylinositol-4,5-bisphosphate 3-kinase;
P-gp- P-glycoprotein; Ras: rat sarcoma virus; pRb- phosphorylated retinoblastoma protein; RBT3- Rice bran tocotrienol; ROS- Reactive Oxygen Species; SREBP-2 -sterol-
regulatory-element-binding protein isoform 2; STAT3- Signal transducer and activator of transcription 3; T3-Tocotrienol; T3E- 6-O-carboxypropyl-alpha-tocotrienol; Tf-
Transferrin; TGF-␤ -Transforming growth factor beta; TG-triglyceride; TRF, Tocotrienol Rich Fraction; UDP-glucuronyltransferase; VEGF-Vascular endothelial growth factor;
VPS- Vacuolar protein sorting-associated protein; WAVE2, Wiskott–Aldrich Syndrome protein-family verprolin-homologous protein 2; XIAP- X-linked inhibitor of apoptosis
protein.
a
␣- T3; b ␤-T3; c ␥-T3; d ␦-T3; e TRF; f RBT3; g T3E; h TRF entrapped ␣-T3; i Oxazine derivatives of ␥- & ␦-T3; j BALB/c mice; k transgenic mice; l athymic nude mice;
m
Sprague–Dawley rats; n xenografts mice; o Orthotopic mice; p C3H/HeN mice; q ddY mice; r Rattus norvegicus; s Mutant mice.
264 B.L. Sailo et al. / Pharmacological Research 130 (2018) 259–272
Fig. 2. Tocotrienols can modulate different molecular targets in various cancers. The figure has been made according to Roskoski et al. [188].
proliferation of breast cancer cells by altering the expression of
oxidative stress modulatory enzymes GPX, SOD, NQO1 and NQO2,
and cell cycle regulatory proteins (Rb/E2F complex, cyclin D1/CDK-
4 and cyclin B1/CDK-1) [64,67]. The anti-proliferative effects of T3
in mammary cancer cells are also associated with suppression of
c-Myc; inhibition in early post-receptor steps involved in cAMP
production upstream from EGF-dependent MAPK and PI3K/Akt
signaling; suppression of Wnt/␤-catenin pathway; inhibition of
Rac1/WAVE2 signaling; decreased AP15 and increased MIG6 genes
and miRNA-429 [41,47,49,51,57,62,74,75,77,182]. Additionally, ␥-
T3 also exerted its anti-proliferative activity by lipid raft disruption
as well as decrease in exosome heregulin content, a potent lig-
and for HER3 and HER4 receptors [44,46]. Interestingly, in vitro
treatment of mammary tumor cells with ␥-T3 resulted in reduced
glycolysis and pAkt/mechanistic target of rapamycin (mTOR) path-
way [52]. Additionally, ␥-T3 also inhibited the mammary cancer
cell growth by inhibiting K-Ras, H-Ras, and pERK expression and
upregulating TGF␤-, Fas- and JNK-signaling pathway [50,82,83].
Moreover, in ER␤-containing breast cancer cells, T3 activated
the ER␤ signaling pathway and enhanced the estrogen-responsive
genes such as MIC-1, subsequently conferring caspase-dependent
apoptosis [70]. Studies have also shown that T3 induce apopto-
sis in breast cancer cells by increasing endoplasmic reticulum (ER)
stress and autophagy [6,59,68,71,144]. In addition to this, T3 also
prompted apoptosis in vitro by inhibiting NF-␬B, PI3K/Akt/mTOR
and subsequent downregulation of FLIP, increase of Bax/Bcl-2 ratio
and PARP cleavage [55,57,75,183]. Another study revealed that the
apoptotic property of ␥-T3 in breast cancer cells is mediated by de
novo ceramide synthesis dependent activation of JNK/CHOP/DR5
signaling [60]. The anti-angiogenic effect of ␦-T3 against breast
cancer was also mediated by its ability to reduce the synthesis
of proangiogenic markers such as IL-8 and VEGF [42,58,69,72,81].
Besides these in vitro studies, several in vivo findings have also
confirmed the anti-cancer activities of T3 against breast cancer.
For instance, it has been successfully proven that T3 increased
tumor latency and reduced the tumor incidence and number in
7,12 dimethylbenz(a)anthracene-induced mammary tumor in rats
[3].
Apart from the T3 isoforms, other formulations of T3 also
exert anti-tumor effects on breast cancer. For instance, tocotrienol
oxazine derivatives inhibited mammary tumor growth by reduc-
ing pAkt, NF-␬B, COX-2, cyclin D1, CDK-2, −4, −6 and increasing
cell-cycle arrest proteins (p21 and p27) [54]. Likewise, another
form of T3, annatto-T3 that comprises of 90% ␦-T3 and 10% ␥-
T3, reportedly delayed the development of mammary tumor and
reduced the number and size of the tumor via enhancing both apo-
ptosis and senescent-like growth arrest in HER-2/neu transgenic
mice [5]. Furthermore, treatment of MCF-7-injected athymic mice
with tocotrienol-rich fraction (TRF) significantly downregulated c-
Myc and CD59 glycoprotein precursor gene involved in the immune
system, thus contributing to its anti-tumor effect [80]. Moreover,
tocomin, which consists of a mixture of naturally occurring T3
and T, induced apoptosis in breast cancer cells [144]. Hence, these
investigations collectively indicate the possible benefits of T3 in
prevention and treatment of breast cancer.
6.2. Colorectal cancer
Research over the past several years has revealed the potential
benefits of T3 for colorectal cancer. Studies have ascertained that
␦-T3 significantly inhibit the growth of colon cancer cells through
the downregulation of Wnt-1, ␤-catenin, c-jun, and cyclin D1 [40].
Similarly, ␥-T3 was also found to impede the proliferation of HT-
29 colon cancer cells via downregulating Bcl-2 and upregulating
Bax and caspase-3 [92]. ␦-T3 was reported to reduce telomerase
activity by suppressing PKC activity in colorectal adenocarcinoma
cells, which led to the downregulation of c-Myc and human tel-
omerase reverse transcriptase (hTERT) expression, thus signifying
its anti-proliferative role [95]. In addition to this, ␥-T3 also signif-
icantly induced apoptosis in vitro and in vivo by downregulating
NF-␬B and its regulated gene products [88,92]. Besides, many
other studies have also reported that T3 repressed colon tumor
growth and induced apoptosis by suppressing pAkt, upregulating
CDK inhibitors (p21, p27), caspase-3, and −9, and deregulating
␤-catenin/Tcf (T-cell factor) signaling [89,90]. Notably, TRF also
induced apoptosis in colon cancer cells by activation of p53 and
 B.L. Sailo et al. / Pharmacological Research 130 (2018) 259–272
alteration of Bax/Bcl2 ratio [96]. Moreover, an in vivo study has
proven that TRF reduced the growth of human colon cancer mice
xenografts via suppression of Wnt pathway [38]. Further, studies
have also demonstrated that ␦-T3 hindered hypoxia-induced VEGF
and IL-8 overexpression and by lowering HIF-1␣, thus consequently
inhibiting angiogenesis in breast cancer cells [93,94]. Collectively,
these studies indicate T3 as promising candidates for the treatment
of colon cancer (Fig. 2).
6.3. Gastric cancer
Increasing lines of evidence has confirmed the potential of T3 for
the prevention and treatment of gastric cancer (Fig. 2). For instance,
␥-T3 was reported to impede the growth of human gastric cancer
in vitro and in vivo by inhibiting NF-␬B pathway [165]. Similarly,
␥-T3 also induced apoptosis in gastric cancer cells by downregulat-
ing Raf-ERK signaling pathway and activating caspase-9 [100,101].
Furthermore, it has been demonstrated that ␥-T3 inhibited HIF-1␣
accumulation and paracrine secretion of VEGF through suppres-
sion of pERK1/2 thus, substantially displaying its chemopreventive
and anti-angiogenic abilities [97]. It has also been revealed that ␥-
T3 downregulated MMP-2, −9 and upregulated tissue inhibitor of
metalloproteinase-1 (TIMP-1) and TIMP-2 in vitro, thus elucidating
its anti-metastatic property against gastric cancer [98].
6.4. Glioblastoma
In glioblastoma, the potential of ␦-T3 is elucidated by its ability
to induce marked cytotoxicity in SF-295 glioblastoma cells in vitro
(Fig. 2) [184]. More notably, all the isoforms of T3 have been shown
to induce apoptosis in glioblastoma in vitro by activating caspase-8
and enhancing mitochondrial cytochrome c (cyt. c) release due to
loss of mitochondrial membrane integrity [102,103]. Likewise, T3
formulation, TRF trapped in transferrin bearing vesicles was found
to remarkably enhance the cytotoxic activity of TRF by more than
100 folds in glioblastoma T98G cells by improving the uptake of
TRF [185]. However, further in vitro and in vivo studies are vital to
determine the underlying mechanism of the anti-cancer effect of
T3 in glioblastoma.
6.5. Leukemia
In leukemia, only a few studies have elucidated the therapeu-
tic action of T3. Yet, it has been found that the three isomers of
T3 (␣-, ␥-, ␦-) exerted marked cytotoxic effect against human T-
cell lymphoblastic leukemia cells [12]. Moreover, ␥-T3 imparted
cytotoxicity in various leukemia cell types including lymphoblas-
tic, myeloblastic and relapsed leukemia, portraying its potential
role in the treatment of leukemia [104]. Reports have indicated
that ␦- and ␥-T3 induced apoptosis in leukemia cells in vitro via
nuclear chromatin condensation and nuclear fragmentation [12].
In addition, studies have revealed that ␥-T3 induced apoptosis in
leukemia cells by inhibiting NF-␬B, activating the caspase cascade,
increasing cyt.c release and Bid cleavage (Fig. 2) [34,104]. Further,
␥-T3 induced apoptosis in HL-60 leukemic cells by downregulating
two survival enzymes, HMGCR and glyoxalase 1 (GLO-1) via inhi-
bition of Ras/Raf/ERK/NF-␬B and Ras/Akt/NF-␬B pathways [167].
Additionally, a mixture of ␦-T3 and its peroxy dimer was reported
to trigger apoptosis via mitochondrial pathway, thus reducing the
growth and survival of leukemia cells [184].
6.6. Liver cancer
In recent years, several studies have confirmed the anti-
cancer effect of T3 against hepatocellular carcinoma (HCC) through
the deregulation of different key signaling pathways (Fig. 2)
265
[10,107,109–111]. The relative anti-proliferative effect of T3 iso-
forms against HCC cells were reported as ␦-T3 > ␤-T3 > ␣-T3 > ␥-T3
[3,111]. ␥-T3 was shown to inhibit the proliferation of HCC cells
by upregulating peroxiredoxin-4 (Prx4) [105]. Additionally, ␥-T3
displayed its anti-proliferative and apoptotic functions in HCC
by upregulation of Bax, caspase-8 and caspase-9; increasing Bid
fragmentation; inhibiting STAT3 and its regulated gene prod-
ucts including Bcl-2, Bcl-xL, survivin, cyclin D1, Mcl-1, and VEGF
[107,110]. Besides, administration of T3 remarkably attenuated
hepatocarcinogenesis induced by diethylnitrosamine (DEN)/2-
acetylaminofluorene (AAF) in rats [114,115]. Administration of
␥-T3 and ␦-T3 also remarkably inhibited the development of HCC in
mouse xenograft and orthotopic models by abrogating Akt/mTOR
signaling pathway [106,109]. Interestingly, both ␥-T3 and ␦-T3
were detected only in tumor tissues, but not in normal tissues,
signifying their distinct specificity to the tumor [109]. Addition-
ally, ␥-T3 also possesses lipid-lowering function in HCC, which may
in part contribute to its anti-cancer activity [108,186]. This lipid-
lowering activity is supported by an in vivo study, wherein ␥-T3
reduced triglyceride (TG) via regulating various lipogenic enzymes
such as fatty acid synthase (FAS), sterol regulatory element-binding
transcription factor 1(SREBF1), stearoyl CoA desaturase 1(SCD1)
and carnitine palmitoyl transferase 1A (CPT-1A) [186]. Besides, T3
was also found to suppress the upstream regulators of lipid homeo-
stasis genes including diacylglycerol O-acyltransferase 2 (DGAT2),
apolipoprotein B (ApoB)-100, SREBP1/2 and HMGCR, resulting in
the reduction of hepatic TGs, cholesterol and very low-density
lipoprotein (VLDL) secretion in HepG2 HCC cells [108]. Hence, these
reports collectively unveiled the potential of T3 in the prevention
and treatment of HCC.
6.7. Lung cancer
In lung cancer, T3 isoforms may serve as the new efficacious
alternatives for successful treatment (Fig. 2). In support of this,
Lim et al. revealed that all the T3 isoforms remarkably induced
apoptosis in lung cancer cells through activation of caspase-8 and
mitochondrial cyt.c release [102,103]. Further, ␦-T3 also exerted
its anti-cancer activity in lung cancer by elevating microRNA,
miR-34a, that led to the downregulation of Notch-1 and its
downstream targets such as Bcl-2, cyclin D1, and survivin [116].
Interestingly, a redox-silent analogue of ␣-T3, 6-O-carboxypropyl-
alpha-tocotrienol (T3E) was found to possess higher anti-cancer
potential than T3 in A549 lung cancer cells [117,118]. Additionally,
studies showed that T3E suppressed hypoxia adaptation of lung
cancer cells through the inhibition of Src-induced Akt activation
and decreased HIF-2␣ [117]. T3E was also reported to induce apo-
ptosis in human lung adenocarcinoma that harbors Ras mutation
[118].
6.8. Mesothelioma
Malignant mesothelioma is an aggressive and highly chemore-
sistant malignancy that requires effective treatment. It has been
shown that T3E induced apoptosis in mesothelioma HT28 cell
through inhibition of Src and Src-independent STAT3 (Fig. 2)
[121]. Similarly, another study showed that T3E induced cyto-
toxicity in human mesothelioma H2452 cells by abrogating
cap-dependent translation complex formation through the inac-
tivation of oncogene Ras [119]. Moreover, T3E also detained
cobalt (II) chloride-induced VEGF expression by downregulating
HIF-2␣ signaling in mesothelioma cells thus, emphasizing its anti-
carcinogenic property [120].
266 B.L. Sailo et al. / Pharmacological Research 130 (2018) 259–272
6.9. Pancreatic cancer
Several in vitro and in vivo studies have evinced the preventive
and therapeutic potential of T3 against pancreatic cancer (Fig. 2)
[125]. For instance, ␥-T3 was found to remarkably suppresses pan-
creatic cancer growth both in vitro and in vivo via inhibition of
the constitutive NF-␬B activation and its regulated gene prod-
ucts such as c-Myc, CXCR-4, cyclin D1, MMP-9, VEGF etc. [127].
Besides, ␦-T3 displayed its chemopreventive activity by inhibit-
ing the progression of pancreatic intraepithelial neoplasm (PIN) in
Kras transgenic mouse model via inhibition of Kras-driven path-
ways such as MEK/ERK, PI3K/Akt and NF-␬B and enhanced Bax and
caspase-3 activities [126]. Further, in vitro as well as in vivo settings
have confirmed that ␦-T3 induced G1 cell cycle arrest by elevating
nuclear accumulation of p27 (Kip1). Moreover, T3 also inhibited
pancreatic cancer cell proliferation via suppression of ErbB2 and
mevalonate pathway, and activation of caspase-dependent pro-
grammed cell death [13,36,128]. Treatment of pancreatic cancer
cells with ␦-T3 activated zinc finger transcription factor, EGR-1
that enhanced the expression of Bax, consequently leading to apo-
ptosis [124]. Further, a recent study has demonstrated that ␦-T3
significantly inhibited the metastasis of pancreatic ductal adeno-
carcinoma (PDAC) and PDAC stem-like cells in vivo [123].
6.10. Prostate cancer
In venture of novel drug discovery for prostate cancer, T3 was
found to have high potential in the prevention and treatment
of prostate cancer (Fig. 2) [136]. In vitro studies showed that ␥-
T3 promoted apoptosis and autophagy in human prostate cancer
cells by elevating intracellular levels of sphingolipid intermediates
(dihydroceramide and dihydrosphingosine) involved in de novo
synthesis of spingolipids. Moreover, supplementation of ␥-T3 also
significantly reduced the tumor growth of LNCaP-xenograft mouse
model [132]. Additionally, it has been shown that annatto-T3
inhibited androgen-independent prostate cancer cell proliferation
through simultaneous inhibition of tyrosine kinase, Src and STAT3
[131]. Further, studies have revealed that ␥-T3 induced apopto-
sis of prostate cancer cells by inhibiting TGF␤2, NF-␬B, EGFR,
Fyn/HIF-1␣ and Id family proteins (Id1 and Id3) and activating JNK-
signaling pathway [129,134,136]. Interestingly, ␥-T3 executed its
anti-invasive effect by suppressing mesenchymal markers and sig-
nificantly improving the expression of E-cadherin and ␤-catenin
[136]. It has also been reported that ␥-T3 substantially attenu-
ated the expression of prostate cancer stem cells (CSC) markers
CD133/CD44, which are predicted to be the main cause of remission
in androgen-independent prostate cancer [135]. Further, T3 was
found to degrade the sterol regulatory element-binding protein-2
(SREBP-2) in prostate cancer cells, thereby reducing their viability
through reduced cholesterol level [133].
Likewise, TRF also portrayed its chemopreventive and therapeu-
tic activities against prostate cancer by inducing cell cycle arrest
and apoptosis in vitro [137]. Moreover, daily supplementation of
TRF to transgenic adenocarcinoma mouse prostate mouse model
(TRAMP) significantly lowered the occurrence of tumor forma-
tion and high-grade neoplastic lesions due to the upregulation of
proapoptotic proteins Bcl-2 antagonist of cell death (BAD), caspase-
3 and CDK inhibitors (p21 and p27) [3,155].
6.11. Skin cancer
Since the past several decades, tocotrienols have been of great
importance in dermatology for their protection against photosen-
sitivity. Recently, T3 have been proven effective against skin cancer
(Fig. 2). For instance, ␦-T3 and its peroxy dimer were found to effec-
tively impede the proliferation of melanoma cells [184]. Moreover,
␦-T3 was shown to induce G1 cell cycle arrest in A2058 and A375
human melanoma cells, via downregulating CDK-4 and activating
caspase-3 [141]. Further, studies have shown that ␥-T3 induced
apoptosis in melanoma cells via suppression of NF-␬B, EGFR, Id
family proteins and JNK signaling pathway [142]. The anti-cancer
effect of ␦-T3 has also been elucidated by its ability to induce apo-
ptosis via ER stress in melanoma both in vitro and in vivo [138].
Additionally, a recent in vivo study showed that intravenous admin-
istration of ␣-T3 entrapped in transferrin-bearing vesicles caused
complete tumor eradication in 60% of B16-F10 melanoma tumor
and extended the survival of mice [187]. Additionally, ␥-T3 treat-
ment halted cell invasion in human melanoma through inhibition
of mesenchymal markers and restoration of E-cadherin and ␥-
catenin [142]. Furthermore, ␦-T3 inhibited melanin formation in
B16 melanoma cells through activation of ERK signaling pathway,
which in turn downregulated melanogenesis-related proteins such
as microphthalmia-associated transcription factor (MITF), tyrosi-
nase and tyrosinase-related proteins, TYRP-1 and TYRP-2 [139].
Furthermore, it was also revealed that tocomin enhanced the
degradation of melanosomes in melanoma cells by upregulating
endosome docking/fusion proteins including syntaxin7, vacuolar
protein sorting-associated protein Vps16, Vps33, and Vps41 [140].
Collectively, these reports have shown the growing potential of T3
for skin cancer treatment.
6.12. Other cancers
Apart from the aforementioned cancers, T3 have high poten-
tial in the prevention and treatment of many other cancers. For
instance, studies showed that ␥-T3 act as a Bcl-2 homology domain
3 (BH3) mimetic in neuroblastoma SH-SY5Y cells by attaching to the
hydrophobic groove of Bcl-2 and promoted apoptosis via enhanc-
ing Bax and caspase-9 [122]. Another study indicated that ␥-T3
abrogated NF-␬B activity in SCC-4 tongue squamous carcinoma
cells thereby, enhancing apoptosis [34]. It was also found that ␦-T3
induced apoptosis via inhibition of STAT3 pathway in human blad-
der cancer [43]. Furthermore, it has been reported that ␣- and ␥-T3
induced apoptosis in HeLa cervical cancer cells via enhancing Bax,
cyt.c release, and IL-6, and downregulating Bcl-2, cyclin D3, CDK6,
and p16 [31,86]. Additionally, ␥- and ␦-T3 also induced apopto-
sis in cervical cancer in vitro by promoting ER stress [87]. Further,
in multiple myeloma, ␥-T3 inhibited NF-␬B and STAT3 and their
regulated gene products such as Bcl-2, cyclin D1 etc. thus, indicat-
ing its potential as an effective treatment alternative for multiple
myeloma patients (Fig. 2) [34,35].
7. Chemosensitizing effect of tocotrienols
Due to the development of chemoresistance in cancer cells, the
quest for finding novel and effective chemosensitizing agents has
never ceased. Recent studies have affirmed the high potential of
T3 in chemosensitizing cancer cells to therapeutic agents through
modulation of various molecular targets (Table 2). For instance,
in vitro and in vivo studies revealed that ␥-T3 sensitized pancreatic
cancer cells to gemcitabine and inhibited pancreatic tumor growth
by downregulating the NF-␬B-mediated inflammatory pathways
linked to tumorigenesis [127]. Apart from gemcitabine, T3 also aug-
mented the chemosensitivity of pancreatic cancer cells to other
drugs such as ferulic acid, lovastatin etc. [128,145]. Synergistic
anti-cancer activities were also observed in prostate cancer upon
combined treatment with T3 and other agents including doc-
etaxel and lovastatin [169,175]. Congregate evidences have shown
that T3 in combination with therapeutic agents such as celecoxib,
curcumin, docosahexanoic acid, epigallocatechin gallate (EGCG),
erlotinib, ferulic acid, gefitinib, oridonin, resveratrol, sesamin,
 B.L. Sailo et al. / Pharmacological Research 130 (2018) 259–272 267

Table 2
Chemosensitizing action of tocotrienols.

Cancer Combination In vitro/ In vivo Mechanism of action Reference

Bladder Cancer ␦-T3 + GEM In vitro ↓STAT3 [43]

Breast Cancer ␦-T3 NE + CUR In vitro ↓NF-␬B [25]
Breast Cancer ␥-T3 + DHA In vitro ↓STAT3 [143]
Breast Cancer Tocomin In vitro ↓PI3K; ↓mTOR [144]
Breast Cancer ␥-T3 + oridonin In vitro ↓Akt/mTOR [7]
Breast Cancer ␦-T3 + ferulic acid In vitro ↑G1 cell cycle arrest [145]
Breast Cancer ␥-T3 + PPAR␥ antagonist In vitro ↓COX-2; ↓PGDS; ↓PGD2 [146]
Breast Cancer ␥-T3 + SU11274 In vitro ↓Akt; ↓STAT1/5; ↓NF-␬B [147]
Breast Cancer TRF + DC+TL In vivo ↑IFN-␥; ↑IL-12 [148]
Breast Cancer ␥-T3 + sesamin In vitro ↓cyclin D1; ↓CDK-2,-4,-6 [149]
Breast Cancer ␥-T3 + PPAR␥ antagonist In vitro ↓Akt [150]
Breast Cancer ␥-T3 + statin In vitro ↓HMGCR [151]
Breast Cancer ␥-T3 + SVA In vitro ↓STAT3 [152]
Breast Cancer ␥-T3 + sesamin In vitro ↓EGF [153]
Breast Cancer ␥-T3 + SU11274 In vitro ↓Met [154]
Breast Cancer Tocomin In vivo ↑BAD [155]
Breast Cancer ␥-T3 + CXB In vitro ↓Akt; ↓NF-␬B [156]
Breast Cancer ␥-T3 + erlotinib In vitro ↓ErbB3; ↓ErbB4 [157]
Breast Cancer ␥-T3 + gefitinib In vitro ↓ErbB3; ↓ErbB4 [157]
Breast Cancer ␥-T3 + gefitinib/ erlotinib In vitro ↓STAT; ↓Akt [158]
Breast Cancer ␥-T3 + statin In vitro ↑p27; ↓cyclin D1; ↓CDK2 [159]
Breast Cancer ␥-T3 + EGCG + resveratrol In vitro ↑NQO1 [160]
Breast Cancer ␥-T3 + statin In vitro ↓pMAPK; ↓JNK; ↓Akt [161]
Colorectal Cancer ␥-T3 + capecitabine In vivo ↓NF-␬B [88]
Colorectal Cancer ␦-T3 + jerantinine B In vitro ↓Caspase-8, -3 [162]
Colorectal Cancer ␥-T3 + ATST In vitro ↓HMGCR [163]
Colorectal Cancer ␥-T3 + ATST + CXB In vitro ↑G0 /G1 phase cell cycle arrest [164]
Colorectal Cancer ␥-T3 + TRAIL In vitro ↑DRs [35]
Gastric Cancer ␥-T3 + capecitabine In vitro ↓NF-␬B [165]
Gastric Cancer ␥-T3 + capecitabine In vivo ↓Ki-67; ↓CD31; ↓NF-␬B [165]
Glioblastoma ␦-T3 + jerantinine B In vitro ↑Caspase-3,-8 [162]
Glioblastoma ␥-T3 + HC In vitro ↑Caspase-3 [166]o
Leukemia ␥-T3 + LVT In vitro ↓NF-␬B [167]
Liver Cancer T3 + EPI-NPs In vitro ↓VEGF [168]
Liver Cancer T3 + EPI-NPs In vivo ↓VEGF [168]
Liver Cancer ␦-T3 + PTX In vitro ↓STAT3 [107]
Liver Cancer ␦-T3 + DOX In vitro ↓STAT3 [107]
Lung Cancer ␦-T3 + cisplatin In vitro ↓Notch-1 [116]
Lung Cancer ␦-T3 + LVT In vitro ↓HMGCR [169]
Mesothelioma TRF + cisplatin In vitro ↓Akt [170]
Mesothelioma ␦-T3 + statin In vitro ↓MVL pathway; ↑caspase-3; ↑ER stress [171]
Oral Cancer ␦-T3 + DTX In vitro ↓NF-␬B [172]
Ovarian Cancer ␦-T3 NE + CUR In vitro ↓NF-␬B [25]
Pancreatic Cancer ␦-T3 + ferulic acid In vitro ↑p21 [145]
Pancreatic Cancer ␦- T3 + GEM In vivo ↓VEGF; ↓pAkt [126]
Pancreatic Cancer ␦- T3 + GEM In vitro ↓NF-␬B [173]
Pancreatic Cancer ␦- T3 + GEM In vivo ↓NF-␬B [173]
Pancreatic Cancer ␦- T3 + GEM In vivo ↓NF-␬B [127]
Pancreatic Cancer d-␦-T3 + LVT In vitro ↓HMGR [128]
Prostate Cancer ␥-T3 + PSP In vitro ↑AMPK; ↓ACC [174]
Prostate Cancer ␥-T3 + DTX In vivo ↓Ki-67; ↓Id1 [175]
Prostate Cancer ␥-T3 + DTX In vitro ↑Caspases; ↓EGFR; ↓NF-␬B [136]
Prostate Cancer ␦-T3 + LVT In vitro ↓HMCGR [169]
Skin Cancer d-␦-T3 + LVT In vitro ↑Caspase-3; ↓HMCGR [141]
Skin Cancer ␥-T3+ ␦-T3+ LVT In vitro ↓HMCGR [169]

Note: ↑- Upregulation; ↓- Downregulation; ACC- acetyl-CoA carboxylase; ALDH- Aldehyde dehydrogenase; AMPK-AMP-activated protein kinase;ATST- atorvastatin; BAD Bcl-
2 antagonist of cell death; CD31- cluster of differentiation 31; COX-2- Cyclooxygenase2; CXB-Celecoxib; DC- dendritic cells; DHA- docosahexanoic acid; DOX-doxorubicin;
DR- death receptor; DTX-docetaxel; EGCG-Epigallocatechin gallate; EGF - Epidermal growth factor; EPI-Epirubicin; G1- Gap1; GEM-Gemcitabine; GLO1: Glyoxalase 1;
HC-hydroxychavicol; HMGCR-HMG-CoA- 3-hydroxy-3-methyl-glutaryl-CoA reductase; IFN␥- Interferon gamma; IL-12-Interleukin 12; JNK - Jun amino-terminal kinases;
LVT-Lovastatin; MAPK- Mitogen-activated protein kinases; MVL-mevalonate; mTOR- mechanistic target of rapamycin; NE-Nanoemulsion; NF-␬B- nuclear factor kappa-
light-chain-enhancer of activated B cells; NPs-Nanoparticles; NQO1- NAD(P)H dehydrogenase quinone 1; PGD2-prostaglandin D2; PGDS -prostaglandin synthase; PI3 K
-phosphoinositide 3-kinase; PPAR␥- Peroxisome proliferator-activated receptor gamma; PSP-Polysaccharopeptide; PTX- paclitaxel; RXR-retinoid X receptor; SCID- severe
combined immunodeficiency; STAT3-Signal transducer and activator of transcription 3; SVA -Simvastatin; T3- Tocotrienol; Tf -Transferrin; THD-thalidomide; TL- Tumor
lysate; Tocomin- Mixed tocotrineols with tocopherols; TPGS-d-␣-tocopheryl polyethylene glycol 1000 succinate; TRAIL-Tumor necrosis factor (TNF)-related apoptosis-
inducing ligand; TRAMP- transgenic adenocarcinoma mouse prostate; TRF- Tocotrienol rich fraction;VEGF- Vascular endothelial growth factor.

statin, etc., considerably sensitized breast cancer cells by down-
regulating Akt, NF-␬B, STAT3 and their associated gene products
(Table 2) [7,25,60,143,145,149,157,156,160]. Moreover, treatment
of bladder cancer cells with ␦-T3 and gemcitabine remarkably
enhanced the potential of gemcitabine [50]. In colorectal can-
cer, T3 exhibited chemosensitizing activity when combined with
other compounds such as atorvastatin, capecitabine, celecoxib, jer-
antinine B, etc. [88,162,163] (Table 2). T3 also sensitized gastric
cancer cells to capecitabine both in vitro and in vivo through down-
regulation of NF-␬B-regulated markers of proliferation, invasion,
angiogenesis, and metastasis [165]. Combinatorial therapy com-
prising of T3 either with jerantinine B or hydroxychavicol induced
apoptosis of glioblastoma cells via enhancing caspase activation
[162,166]. Further, combination of T3 with chemotherapeutic
268 B.L. Sailo et al. / Pharmacological Research 130 (2018) 259–272
Table 3
Clinical Studies of Tocotrienols against Different Cancers.
Cancer Phase No. of pts Dose; duration
Breast Cancer Pilot trial 248 200 mg/daya ; 5yrs
Breast Cancer II 78 900 mg/dayc
Colorectal Cancer II 70 900 mg/dayb
Lung Cancer III 190 900 mg/dayd
Ovarian Cancer II 23 900 mg/daye
Ovarian Cancer II 34 900 mg/day
Pancreatic Cancer I 25 200–1600 mg/day; 2 weeks
a
Given in combination with tamoxifen.
b
Given in combination with FOLFOXIRI (5-fluorouracil, oxaliplatin, irinotecan).
c
Given in combination with neoadjuvant chemotherapy (epirubicin, cyclophosphamide, docetaxel, trastuzumab, pertuzumab).
d
Given in combination with cisplatin, vinorelbine, carboplatin.
e
Given in combination with bevacizumab.
agents such as paclitaxel, doxorubicin, and nano-encapsulated
epirubicin enhanced apoptosis in liver cancer cells by downreg-
ulating VEGF and STAT3 [107,168]. Additionally, in lung cancer and
mesothelioma, it has been reported that T3 sensitized the can-
cer cells to cisplatin and statin [116,169]. In vitro treatment of
oral cancer cells with ␦-T3 and docetaxel significantly enhanced
the chemosensitivity by downregulating NF-␬B-regulated gene
products concomitant with inhibition of apoptosis [172]. Further,
combination of ␦-T3 and lovastatin synergistically induced apo-
ptosis in human melanoma cells by inhibiting HMCGR activity
[141] (Table 2). Hence, these preclinical findings have provided the
potential of T3 isoforms as novel chemosensitizing agents for the
effective treatment of cancer.
8. Clinical studies on tocotrienols- completed and ongoing
Promising results from preclinical studies have encouraged few
clinical studies where the efficacy of T3 against different cancers
has been assessed. So far, only two clinical studies have been
completed, and five clinical trials are ongoing to evaluate the ther-
apeutic role of tocotrienols in breast, colorectal, lung and ovarian
cancers (Table 3).
The first clinical trial of T3 on cancer was published in 2010.
This study was carried out to assess the efficacy of T3 in combi-
nation with the drug, tamoxifen for breast cancer. In this study,
240 women, aged between 40 and 60 years with early breast
cancer received TRF and tamoxifen for five years. However, the
results were not significant and showed no association between
the adjuvant T3 therapy and breast cancer specific survival [176].
Subsequently, a phase I trial was conducted in 25 patients with
pancreatic ductal neoplasia. In this study, the patients received an
escalating dose of 200–3200 mg of ␦-T3 for two weeks prior to
surgery and one dose on the day of surgery. It was found that a dose
of 200–1600 mg of ␦-T3/daily for two weeks prior to surgery was
well tolerated, attained bioactive levels in the blood, and remark-
ably instigated apoptosis of neoplastic cells, thus suggesting the
therapeutic potentials of ␦-T3 for pancreatic cancer [27]. In addi-
tion, several ongoing clinical studies of T3 are being carried out in
Vejle hospital, Department of Oncology, Vejle, Denmark. For exam-
ple, a phase II clinical study is being conducted with breast cancer
patients to investigate the effect of T3 in combination with neoad-
juvant chemotherapy. In this study, a dose of 300 mg × 3/day of T3 is
given with chemotherapeutic agents such as epirubicin, docetaxel,
cyclophosphamide, trastuzumab and ertuzumab. Further, another
ongoing phase II study with metastatic colorectal cancer patients
aims to determine whether T3 can decrease the side effects of FOL-
FOXIRI (5-fluorouracil, oxaliplatin, irinotecan). In this particular
trial, 70 colorectal adenocarcinoma patients are orally adminis-
tered with 900 mg/day of T3 in combination with FOLFOXIRI. In
addition, the chemosensitizing effect of T3 has been carried out in
two ongoing breast cancer phase II trials. Further, a phase III trial
Outcome/ status Reference
No significant outcome [176]
Ongoing [177]
Ongoing [177]
Ongoing [177]
Ongoing [177]
Ongoing [177]
Well tolerated; reached bioactive levels in blood [27]
involving 190 patients with advanced non-small cell lung cancer
is being carried out to evaluate the synergistic potential of ␦-T3
in combination with standard chemotherapy. In addition, another
phase II clinical trial is also being undertaken wherein advanced
ovarian cancer patients are administered 300 mg × 3/day of T3 with
bevacizumab. Similarly, in another ongoing phase II clinical study,
a daily dose 900 mg of T3 is orally administered to ovarian cancer
patients until progression or unacceptable toxicity [177]. Comple-
tion of these ongoing trials will provide us a solid foundation for
further studies on the efficacy of tocotrienols for the management
of different cancers.
9. Conclusions and future prospect
Preclinical studies conducted over the past several years have
established T3 as novel, safe, and efficacious multi-targeted anti-
cancer agents. It has been well proven that T3 have higher efficacy
and health benefits when compared to T. Comprehensive studies
have substantiated the potential of T3 in modulating numerous key
signaling pathways involved in the development and progression
of cancer, thus encouraging their use as mono-targeted therapy as
well as combinatorial therapy with other chemotherapeutic drugs.
Besides, several clinical studies have confirmed the safety and effi-
cacy of T3. However, potential of T3 are often constrained by their
poor solubility and low bioavailability. In recent years T3 are formu-
lated in the form of nanoemulsions, liposomes, micelles complexes
as well as lipid conjugates with chemotherapeutic drugs to enhance
their bioavailability and efficacy. However, these formulations still
demand further investigations. Thus, in depth studies to find effi-
cient delivery systems and increase the bioavailability of T3 are of
prime importance [4,14]. Additionally, scarcity of T3 in nature and
their cost of extraction also increase their limitation, making T3
isoforms expensive compounds. Hence, further research for better
extraction and synthesis methods of T3 isoforms is vital to attain
their maximum value. Also, extensive investigation is warranted
to demarcate the different mechanisms of actions associated with
different isoforms of T3 to establish them as alternatives in cancer
therapeutic cache [17]. Furthermore, till today, only two clinical
trials of T3 on cancer patients have been completed, out of which
T3 was shown to have no significant outcome in breast cancer
patients even though preclinical settings have revealed the incred-
ible potential of T3 against breast cancer. Hence, further preclinical
and clinical studies are unquestionably indispensable in future to
establish T3 as safe and promising agents, opening new avenues for
the prevention and treatment of different cancers.
Acknowledgement
This work was supported by BT/529/NE/TBP/2013 awarded to
Dr. Ajaikumar B. Kunnumakkara. The author Bethsebie Lalduhsaki
Sailo acknowledges DST-INSPIRE for providing the fellowship. The
 B.L. Sailo et al. / Pharmacological Research 130 (2018) 259–272
author, Kishore Banik acknowledges UGC, New Delhi for providing
the fellowship.
Conflict of interests
The authors declare that there are no conflict of interests asso-
ciated with the manuscript.
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